Gene therapy for late infantile neuronal ceroid lipofuscinosis: neurosurgical considerations. Academic Article uri icon

Overview

MeSH

  • Atrophy
  • Child
  • Equipment Design
  • Frontal Lobe
  • Humans
  • Image Processing, Computer-Assisted
  • Injections
  • Magnetic Resonance Imaging
  • Neuronavigation
  • Parietal Lobe
  • Postoperative Complications
  • Trephining

MeSH Major

  • Aminopeptidases
  • Brain
  • Dependovirus
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • Gene Transfer Techniques
  • Genetic Therapy
  • Neuronal Ceroid-Lipofuscinoses
  • Serine Proteases

abstract

  • The authors conducted a phase I study of late infantile neuronal ceroid lipofuscinosis using an adenoassociated virus serotype 2 (AAV2) vector containing the deficient CLN2 gene (AAV2(CU)hCLN2). The operative technique, radiographic changes, and surgical complications are presented. Ten patients with late infantile neuronal ceroid lipofuscinosis disease each underwent infusion of AAV2(CU)hCLN2 (3 x 10(12) particle units) into 12 distinct cerebral locations (2 depths/bur hole, 75 minutes/infusion, and 2 microl/minute). Innovative surgical techniques were developed to overcome several obstacles for which little or no established techniques were available. Successful infusion relied on preoperative stereotactic planning to optimize a parenchymal target and diffuse administration. Six entry sites, each having 2 depths of injections, were used to reduce operative time and enhance distribution. A low-profile rigid fixation system with 6 integrated holding arms was utilized to perform simultaneous infusions within a practical time frame. Dural sealant with generous irrigation was used to avoid CSF egress with possible subdural hemorrhage or altered stereotactic registration. Radiographically demonstrated changes were seen in 39 (65%) of 60 injection sites, confirming localization and infusion. There were no radiographically or clinically defined complications. The neurosurgical considerations and results of this study are presented to offer guidance and a basis for the design of future gene therapy or other clinical trials in children that utilize direct therapeutic delivery.

publication date

  • August 2010

has subject area

  • Aminopeptidases
  • Atrophy
  • Brain
  • Child
  • Dependovirus
  • Dipeptidyl-Peptidases and Tripeptidyl-Peptidases
  • Equipment Design
  • Frontal Lobe
  • Gene Transfer Techniques
  • Genetic Therapy
  • Humans
  • Image Processing, Computer-Assisted
  • Injections
  • Magnetic Resonance Imaging
  • Neuronal Ceroid-Lipofuscinoses
  • Neuronavigation
  • Parietal Lobe
  • Postoperative Complications
  • Serine Proteases
  • Trephining

Research

keywords

  • Clinical Trial, Phase I
  • Journal Article

Identity

Language

  • eng

PubMed Central ID

  • PMC3763702

Digital Object Identifier (DOI)

  • 10.3171/2010.4.PEDS09507

PubMed ID

  • 20672930

Additional Document Info

start page

  • 115

end page

  • 122

volume

  • 6

number

  • 2